1 Kardiovaskulær og Renal Forskning, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU2 Pathology, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU3 Det Sundhedsvidenskabelige Fakultet, SDU4 Kardiovaskulær og Renal Forskning, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU5 Pathology, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
The postnatal rat kidney is highly susceptible to Lithium (Li+), which leads to significant tissue injury. We hypothesized that Li+ impairs development of the kidney through entry into epithelial cells of the distal nephron, inhibition of Glycogen Synthase Kinase-3β (GSK-3β) through phosphorylation on serine9 (pGSK-3β)and subsequent epithelial to mesenchymal dedifferentiation (EMT). GSK-3β immunoreactive protein was associated with collecting ducts in developing and adult human and rat kidney. Total GSK-3β protein abundance was stable in medulla while it decreased in cortex in the postnatal period in rat kidney. In contrast pGSK-3β protein abundance decreased significantly with development in cortex and medulla. Food pellets containing Li+ was given to female Wistar rats with litters through postnatal (P) days 7-29. At P29, plasma Li+ in offspring was 0.99 mmol/L and quantitative stereological analysis showed reduced total kidney volume and reduced cortex and outer medulla volumes compared to control. At P70, 5 weeks after Li+ withdrawal, stereological analysis showed a persisting reduction of outer medulla volume compared to control kidneys. Li+ treatment (P7-P29) increased pGSK-3β protein level significantly whereas total GSK-3β abundance was unaltered. Li+ treatment increased α-Smooth Muscle Actin (α-SMA) protein level significantly whereas E-cadherin expression was unaltered. In summary, Li+ treatment impairs postnatal development of the kidney cortex and outer medulla and increases pGSK-3β abundance in collecting duct. The data are compatible with the notion that increased GSK-3β activity in the postnatal kidney medulla is necessary for kidney development.